Because of the dramatic improvement in survival among people with HIV infection, premature coronary artery disease (CAD) has become one of the most serious clinical challenges facing HIV-infected individuals. Even so, the combined effects of HIV infection, chronic substance use, and prolonged antiretroviral therapy (ART) exposure have never been thoroughly investigated. In the past 15 years, with a very low lost-to-follow-up rate (<3.5% per year), we have built a cohort of 1,400 cardiovascularly asymptomatic African Americans (AAs) in Baltimore to investigate the effects of HIV infection, chronic cocaine use, and prolonged ART exposure on subclinical CAD. We have collected questionnaire data, physical examination data, biologic specimens, laboratory data, clinical data, and cardiac CT data from the study participants. Cocaine abuse is highly prevalent and serves as a powerful co-factor for HIV exacerbation in AAs. Epigenetic alterations in cocaine abuse and HIV infection determine expression of several critical genes. The objectives of this project are to (1) maintain and expand our cohort of mainly AAs with HIV infection (some HIV negative as controls) and consolidate infrastructure to provide a platform for a wide range of research efforts; (2) examine longitudinally the effects of chronic cocaine use, and prolonged ART exposure on the development and progression of subclinical/clinical CAD in HIV-infected AAs; and (3) conduct two pilot studies to investigate epigenetic changes in relation to HIV-associated neurocognitive impairment and subclinical coronary atherosclerosis. We will explore the epigenetic mechanisms including histone modification and DNA methylation contribute to drug-induced gene expression profile in HIV-infected AAs. The proposed specific aims are:(1) with a one-year funding, we propose to maintain/build the existing cohort as a platform for independently funded studies and other collaborative research on AIDS-related and HIV-associated non-AIDS conditions such as cardiovascular/cerebrovascular disease, neurologic and psychiatric status, and other outcomes, (2) due to limited funding for one year, we will examine longitudinally (only two visits: a previous visit, and a new visit) how ART-induced subclinical and clinical coronary artery disease is exacerbated by chronic cocaine use in African Americans (AAs) with HIV infection, (3) to investigate how HIV-associated neurocognitive impairment is impacted by chronic cocaine use, (4) to investigate epigenetic changes in relation to HIV-associated neurocognitive impairment, and (5) to investigate epigenetic changes in relation to HIV-associated subclinical atherosclerosis. These aims can be addressed only with continued follow-up of this extremely well-characterized cohort. With longitudinal data, including advanced imaging data, the proposed study will play a crucial role in studies designed to lead to better understanding and preventive measures for CAD in those with HIV infection, cocaine use, and prolonged ART exposure.